There is an epidemic of prediabetes and type 2 diabetes mellitus among the severely mentally ill, with prevalence twice that of the general population. One source of risk for metabolic disorders is related to the antipsychotic medications widely used for the treatment of schizophrenia and other major mental disorders, with ample data showing that antipsychotic exposure may be associated with insulin resistance and the development of diabetes mellitus. Emerging data also indicate that antipsychotics with high metabolic risk may have weight-independent effects on insulin sensitivity, effects that can be seen after single doses in laboratory animals, but these findings have yet to be successfully demonstrated in a human model. The development of a human model using single-dose antipsychotic exposure avoids the expense and ethical issues inherent in chronic human exposure to metabolically higher risk medications, the psychiatric risk of antipsychotic switch studies in schizophrenia patients, and the difficulty in obtaining neuroleptic naove schizophrenia patients to eliminate the confounding effects of drug exposure. Prior attempts to study the metabolic effects of antipsychotics in nonpsychotic subjects failed to elucidate the known effects of these agents, in part related to the use of individuals with extremely low risk for metabolic dysfunction. Successful metabolic research in nonmentally ill human individuals requires the carefull selection of candidate subjects with enough predisposition towards developing diabetes mellitus to permit the demonstration of acute metabolic effects of antipsychotics. The purpose of this study is to demonstrate the feasibility of a human model for such research using nonmentally ill subjects exposed acutely to antipsychotics using gold standard methods in endocrine research for assessing whole body and hepatic insulin sensitivity, namely the euglycemic-hyperinsulinemic clamp with labeled glucose tracer (to measure hepatic glucose production). This randomized, prospective trial will examine the comparative effects of two antipsychotics (olanzapine and aripiprazole) with disparate metabolic effects to assess the feasibility of single-dose metabolic research, and the comparative impact of these two medications on metabolic parameters. The successful demonstration of acute antipsychotic metabolic effects in subjects free from confounding issues, such as the impact of prior psychotropic exposure, offers significant promise for the elucidation of underlying mechanisms that cause metabolic problems in antipsychotic-exposed patients. A better understanding of these mechanisms may offer significant clinical benefit in two ways: 1) by allowing the identification of patients at low risk for metabolic effects who can safely use certain medications, and 2) facilitating the development of antipsychotics with the efficacy of agents like clozapine, but free of the metabolic liability. These goals also support the NIH Roadmap initiatives in building cross-disciplinary research, and developing interdisciplinary research models to address the complex clinical problems such as metabolic dysfunction among patients exposed to antipsychotic medications. PUBLIC HEALTH RELEVANCE: Atypical antipsychotics are widely used for the treatment of schizophrenia and other mental disorders, but have been linked to adverse metabolic effects, such as new onset diabetes mellitus. The absence of a feasible human model to study these issues has been a roadblock to the discovery of mechanisms that underlie these metabolic problems during antipsychotic treatment. The purpose of this project is to study a novel model for exploring the acute metabolic impact of antipsychotics that minimizes the subject risks seen in prior human studies, and is more easily replicated. [unreadable] [unreadable] [unreadable]